Graham et al.

, J Sports Med Doping Stud 2012, 2:3

Sports Medicine & Doping Studies http://dx.doi.org/10.4172/2161-0673.1000113

Review Article Open Access

Exercise, Science and Designer Doping: Traditional and Emerging Trends

Graham MR1*, Davies B2, Grace FM3 and Baker JS3
1
Sport and Exercise Science, Institute of Health, Medical Science and Society Science, Glyndwr University, Wrexham, Wales, UK
2
Health and Exercise Science, University of Glamorgan, Pontypridd, Wales, UK
3
Exercise Science, University of the West of Scotland, Hamilton, Scotland

Abstract
The list of doping agents is enormous, and for the majority, any beneficial sporting effect is contentious. WADA
and UK Anti-Doping have difficulty detecting the peptide hormones, Growth Hormone (GH), insulin and Erythropoietin
(Epo), because they require blood analysis. Only in the last two years has an athlete been convicted of taking GH,
which is still being used as a doping agent because the window for detection is so brief. This positive test was not
contested, which suggests that science may be winning the war on drugs. Athletes appear to have ceased taking
insulin, because of its life-threatening acute effects, and in recent years no adverse analytical findings have been
reported for this drug.
“Older” doping agents, which are known to enhance performance in sport, include testosterone and their
derivatives, anabolic steroids.
The pharmaceutical industry continues to manufacture new medicines, pushing back the boundaries in combating
wasting disease states and the ageing process, but is inadvertently producing the latest generation of doping agents.
This will challenge anti-doping scientists.
WADA’s banned list also includes insulin-like growth factor-1, fibroblast growth factors, hepatocyte growth factor,
mechano growth factors, platelet-derived growth factor, vascular-endothelial growth factor which may promote muscle,
tendon or ligament development, vascularisation, energy utilisation, regenerative capacity and fibre type. Athletes will
use whatever they believe works, but can only use what is available. Internet companies offer these anabolic products
that but their veracity cannot be proven.
There are questions that need to be answered? Are these products available to athletes, do they enhance
performance, are athletes really taking them and are they so difficult to detect. The internet has made them available
to anyone with a credit card and it appears that if they are cycled correctly, unless an athlete is caught in possession
of them, the opportunity of proving a case of doping is almost impossible.

Keywords: Anabolic steroids; Epo; GH; IGF; Insulin; Mechano (IOC) established a Medical Commission which provided three
growth Factor; Myostatin fundamental principles: protection of the health of athletes, respect for
medical and sport ethics, and equality for all competing athletes [6].
Introduction
At that time the list of banned substances included narcotic
The involvement of sport’s scientists in elite sport has led them analgesics, stimulants and alcohol. Although it was suspected that
to develop improved nutrition, physiological and psychological AAS were being used at this time, testing methods were insufficiently
techniques but also to be significantly implicated in the development
developed to warrant their inclusion. The first compulsory doping
and use of performance enhancing drugs [1]. East German scientists
controls were at the Winter Olympic Games in Grenoble, France in
were involved in the state-sponsored systematic doping of athletes
1968 [7].
in the former East Germany [2]. American scientists have also been
concerned in the dissemination of performance and image enhancing In the 1984 Olympics, some team doctors were involved in exploiting
drugs used in international sport. Dr John Ziegler, originally developed the doping regulations. Team doctors had to fill in declarations for all
the Androgenic Anabolic Steroid (AAS) Methandrostenolone athletes using specific drugs perceived to be performance enhancing. If
(Dianabol) which was released in the USA in 1958 by the pharmaceutical competitors produced a doctor’s certificate stating that they needed a
giant, Ciba. Ziegler pioneered its athletic use as an aid to muscle growth drug for health reasons, they would not be disqualified, if drug checks
by bodybuilders, administering it to USA weightlifting champion Bill
proved positive. Following a large number of positive urinalyses some
March in 1959 when he was the physician to the USA Weightlifting
teams provided medical certificates covering the whole team [8]. This
team [3]. This appears to be the first documented use of AAS in sport
identified the deception that physicians were prepared to be concerned
[4]. The emphasis and rewards placed on winning and breaking world
records has made this liaison between sporting performance and
science almost inextricable.
*Corresponding author: Graham MR, Sport and Exercise Science, Institute of
In 1960, Danish cyclist, Knut Jensen, was the first athlete to die in Health, Medical Science and Society Science, Glyndwr University, Wrexham,
Olympic competition due to doping, during the 100 km team time trial Wales, UK, E-mail: [email protected]
race. His autopsy revealed traces of amphetamine [5]. British cyclist Received September 12, 2011; Accepted May 29, 2012; Published May 31, 2012
Tom Simpson, whose motto was “if it takes ten to kill you, take nine
Citation: Graham MR, Davies B, Grace FM, Baker JS (2012) Exercise, Science
and win.....” was the first death caused by doping in the Tour de France, and Designer Doping: Traditional and Emerging Trends. J Sports Med Doping Stud
in 1967. Two tubes of amphetamines and a further empty tube were 2:113. doi:10.4172/2161-0673.1000113
found in the rear pocket of his racing jersey. His autopsy revealed traces
Copyright: © 2012 Graham MR, et al. This is an open-access article distributed
of amphetamine, alcohol and the diuretic frusemide. under the terms of the Creative Commons Attribution License, which permits
unrestricted use, distribution, and reproduction in any medium, provided the
In 1967 to combat doping, the International Olympic Commitee original author and source are credited.

J Sports Med Doping Stud Volume 2 • Issue 3 • 1000113

ISSN: 2161-0673 JSMDS, an open access journal
Citation: Graham MR, Davies B, Grace FM, Baker JS (2012) Exercise, Science and Designer Doping: Traditional and Emerging Trends. J Sports Med
Doping Stud 2:113. doi:10.4172/2161-0673.1000113

Page 2 of 9

in to win at any cost. One of the drugs in this instance was a beta- cleared from the body between 2-14 days following withdrawal, and
blocker, which could in fact impede performance, in endurance events. water soluble “injectables” after 4 weeks, it is possible to use these agents
during periods of intensive training and test negative. In 1982, the IOC
Convictions of celebrity athletes for doping offences and their
test for detection of testosterone administration was based on the GC/MS
subsequent confessions have identified the extent of their subterfuge
[9-14]. determination of the urinary ratio of testosterone (T) to its 17 α-epimer,
epitestosterone (E), following glucuronide hydrolysis, commonly
The authorities are partly to blame. Zero tolerance and a lifetime ban referred to as T/E ratio [20]. In healthy men and women, the T/E ratio
for any offence, would be a far greater deterrent than a two year ban, for is approximately 1. Supraphysiological doses of testosterone cause an
the first Adverse Analytical Finding (AAF), a two year to lifetime ban increase in the ratio as a result of increased excretion of testosterone.
for second or subsequent violations and a four year to lifetime ban for The T/E ratio may be augmented as a consequence of dose-dependent
trafficking. WADA have written extensive documents, euphemising inhibition of testicular steroidogenesis. When supraphysiological doses
the fact that they are prepared to offer “deals” with offending dopers of testosterone are taken, suppression of luteinising hormone secretion
in an attempt to identify the provenance of these doping agents and decreases urinary epitestosterone glucuronide. The WADA Medical
suppliers [15]. Code stipulates that if a ratio of T/E is greater than 4, it is mandatory
When rewards for athletic success are so great, human nature that the relevant medical authority conducts an investigation before
is such that certain individuals will always succumb to fruit of the the sample is declared positive. Investigations include a review of T/E
forbidden tree. Athletes are more concerned with failure than they are results from previous tests, subsequent tests and also results of any
about adverse health effects as a consequence of cheating [16]. serum endocrine investigations. The athlete will then be monitored
at least monthly for three months. However, an athlete may have a
Doping could be halted overnight if the sanctions were severe
physiological increased ratio being a natural biological outlier [21]. In
enough. However, where would that leave the billion dollar WADA
the case of a T/E ratio ≥4, isotope ratio mass spectrometry (IRMS) can
administrative machine?
determine the exogenous administration [22].
Specific questions need to be answered. Do these agents really
enhance performance? Are they harmful? Are they detectable? This Do AAS Enhance Performance?
short review will assess current doping agents being used, whether they AAS were proven only as recently as 1996 to increase muscle mass
have the desired effect, and whether athletes can beat “the test”. and strength in adult males [23]. Extrapolation of these effects to the
sporting arena is not in doubt and is the reason why they are still the
Anabolic Steroids most common AAF in anti-dope testing today [24].
Androgenic Anabolic Steroids (AAS) are a group of synthetic
The prevalence of AAS use, the risks to an athlete’s health and the
compounds similar in chemical structure to the natural anabolic
methods used to detect them by urinalysis are well documented in the
steroid testosterone (Figure 1) [17]. In 1969, the first application
literature [25].
of RadioImmunoAssay (RIA) for the measurement of steroids in
biological fluids was published [18]. Accessibility
The IOC Medical Commission acted by the introduction of AAS The price of genuine AAS and their restriction due to their
as a banned class in 1974 following the development of a screen for classification under the misuse of drugs act, 1971, has initiated an
the 17α-alkylated orally active drugs, in the biological medium of enormous counterfeit market. The most popular AAS are presented
urine. Any presumptive positive samples could then be analysed by in 10 ml multi-dose vials, claiming to have very high concentrations
gas chromatography-mass spectrometry (GC-MS) for confirmatory of active ingredients. Multiple websites offer AAS, at varying prices
identification [19]. The advantage that GC/MS screen provided resulted [26]. A large majority of these counterfeit products are made in
in the replacement of RIA, which is today’s accepted method. unlicensed laboratories in countries where the law is more permissive
AAS detection has always been problematic. They are abused by than the UK or USA, such as Mexico, China and Thailand. The dangers
athletes during training and are not taken during the actual competitive associated with such products are patently obvious. Table 1 identifies
period, in an attempt to avoid detection. Since oral preparations are genuine prescription medicines, which are AAS and have been used as
doping agents and the cost to the National Health Service in the UK.
Table 2 identifies potential counterfeit AAS that are currently used by
Esterification confers depot
Introduction of double bond
Removal of the
angular methyl group activity for i.m. administration bodybuilders, weightlifters, power lifters and rugby players, available
Attachment of from other sources, including internet companies.
methyl group
OH
Attachment of various
groups at C-2 Attachment of 17 α-alkyl
group confers oral activity
Growth Hormone (GH)
17
C D
The somatotroph cells in the anterior pituitary synthesise and secrete
Attachment of pyrazole 2
1 the polypeptide human Growth Hormone (hGH) which appears to
B
ring to the A-ring
3
A
4 7 have been isolated in 1944 [27] and then manufactured by recombinant
O
Attachment of 7 α-methyl
DNA technology in the mid 1980’s producing recombinant human
group Growth Hormone (rhGH) [28]. It is secreted as a 191-amino-acid,
Attachment of chlorine or
4-helix bundle protein, weighing 22,000 daltons (70-80%) and a less
hydroxyl group abundant 176-amino-acid form, weighing 20,000 daltons (20-30%)
Figure 1: The structure of testosterone and structural modifications to the A- [29]. See figure 2 for GH three-dimensional configuration.
and B-rings of this steroid molecule that increase anabolic activity. Substitution
at C-17 confers oral or depot activity [17]. Athletes have been trying to extrapolate postulated benefits to
IM = intramuscular. achieve physical improvement since 1982 [30].

J Sports Med Doping Stud Volume 2 • Issue 3 • 1000113

ISSN: 2161-0673 JSMDS, an open access journal
Citation: Graham MR, Davies B, Grace FM, Baker JS (2012) Exercise, Science and Designer Doping: Traditional and Emerging Trends. J Sports Med
Doping Stud 2:113. doi:10.4172/2161-0673.1000113

Page 3 of 9

Product Pharmaceutical Manufacturer Manufacturers Price Mode of delivery

Sustanon 250®
(testosterone propionate 30 mg, testosterone
net price
phenylpropionate 60 mg, testosterone isocaproate 60 mg, Organon Intramuscular
1-mL amp =£2.45
and testosterone decanoate 100 mg)
250 mg/1 ml
Testosterone enantate Non-Proprietary net price
Intramuscular
250 mg/1 ml (Generic) 1-mL amp = £13.33
Deca-Durabolin®
Organon net price
(nandrolone decanoate) Intramuscular
1-mL amp = £3.17
50 mg/1 ml
Testosterone propionate (Virormone®) net price
Nordic Intramuscular
50 mg/1 ml 2-mL amp = £4.50
Testosterone undecanoate (Nebido) net price
Bayer Schering Intramuscular
250mg/1 ml 4-mL amp = £76.70
Restandol® Testocaps net price
(testosterone undecanoate) Organon 30-cap pack = £8.55; Oral
40 mg/capsule 60-cap pack = £17.10
Pro-Viron®
Net price
(mesterolone) Bayer Schering Oral
30-tab pack = £4.19
25 mg/tablet
Striant® SR
net price Mucoadhesive buccal tablets /
(testosterone tablet) (The Urology Co. )
60-tab pack = £45.84 Sublingual
30 mg/tablet
Intrinsa® net price
(Testosterone patch) Warner Chilcott 8-patch pack Transdermal
(self-adhesive, releasing testosterone 300 mcg/24 hours) = £26.91
Testim® net price
(Testosterone gel Ferring (testosterone 50 mg/5 g tube) Transdermal
50 mg/5 gm) 30-tube pack = £32.00
Testogel® net price
(Testosterone gel) Bayer Schering 30-sachet pack Transdermal
50 mg/5 gm sachet = £31.11
Tostran® net price
(testosterone gel 2%) ProStrakan 60-gm multidose dispenser = Transdermal
(10 mg/metered application) £26.67
net price
Testosterone
Organon 100 mg = £7.40; Implant
100 mg
200 mg = £13.79
Table 1: Prescription only Medicines, Testosterone and Esters used in hormone replacement.

Its powerful effects in GH Deficiency (GHD) were proven in 1989 endurance performance, power and strength [36]. The beneficial effects
[31] and these effects were also experienced in elderly men aged 60 were believed to have occurred because of AAS withdrawal inducing
years of age in 1990 [32]. a state of catabolism, which was rectified by rhGH administration.
Catabolism was identified by low results for insulin-like growth
Its seizure of rhGH in the possession of Chinese swimmers at
factor-1 (IGF-1) the surrogate marker of endogenous GH production
the 1998 World Swimming Championships and again discovery of
[37]. Such research suggests that senescence or pharmaceutically
possession by cyclists at the Tour de France cycling event in 1998 have
proven its abuse at an elite level [33]. induced catabolism are two conditions that may benefit from rhGH
administration, in a sporting context.
Does rhGH Enhance Performance?
Detection of rhGH
Extensive research with rhGH on non-competitive athletes has
produced controversial results. Contemporary evidence appears to The current official method employed by WADA cannot detect
contradict the proven anabolic effect of rhGH in deficiency, in drug pituitary hGH by blood or urine. This is no longer derived from
naïve healthy human muscle, in males (mean age of 28 years) [33]. Nor cadaver pituitaries by pharmaceutical companies because of the
did it appear to improve athletic performance in females (mean age of risk of Creutzfeldt-Jakob disease transmission. This is an incurable
25 years) and males (mean age of 27 years) [34]. degenerative neurological disorder transmitted by contaminated
harvested human brain products that is invariably fatal. It has been
Administration of rhGH caused no further increase in muscle mass shown to result from use of hGH obtained from the pituitary glands
or strength, than that provided by resistance training in experienced of persons who died from it. However unless an athlete can obtain and
male weight lifters (mean age of 22 years) attempting to further increase purify cadaver pituitary, rhGH is the only form of the agent available.
muscle mass [35]. There were unsubstantiated allegations of the arrest of a Russian who
Difficulties appear to have arisen in targeting an appropriate dose had more than1000 human pituitary glands in his home in Moscow,
range that would promote muscle protein anabolism and not cause just prior to the Sidney Olympics in 2000.
adverse effects, counteracting performance enhancement.
rhGH is currently undetectable by urinalysis. Detection is by
In contrast, a study was conducted on experienced male weight blood analysis and relies on the difference between the isoforms of
lifters, who were former AAS users (mean age of 31 years) that improved hGH. Endogenous hGH comprises 70% 22 Kilodaltons (KDa) and

J Sports Med Doping Stud Volume 2 • Issue 3 • 1000113

ISSN: 2161-0673 JSMDS, an open access journal
Citation: Graham MR, Davies B, Grace FM, Baker JS (2012) Exercise, Science and Designer Doping: Traditional and Emerging Trends. J Sports Med
Doping Stud 2:113. doi:10.4172/2161-0673.1000113

Page 4 of 9

Black-market Black-market Black-market

Product
Pharmaceutical Manufacturer Wholesale Price Retail Price
Anabolic Steroid Hormones (IM)
Sustanon
Generic (non-proprietary)/ Organon (Pakistan) £1.75 £2.5
250 mg (1 ml)
Testosterone enanthate Generic (non-proprietary)/ Apex/Prochem/Dragon/British Dragon,
£2 £3.5
250 mg (1 ml) Pharmaceuticals
Testosterone 400
Generic (non-proprietary)/ Apex/Prochem/Dragon/British Dragon,
(testosterone propionate, cypionate and enanthate) £18 £30
Pharmaceuticals
(10 mls)
Nandrolone 300 mg/ml Generic (non-proprietary)/ Apex/Prochem/Dragon/British Dragon,
£19 £30
(10 mls) Pharmaceuticals
Masteron (Drostanolone Propionate)
Generic (non-proprietary)/ Apex/Prochem/Dragon/British Dragon,
100mg/ml (10 mls) £20 £30
Pharmaceuticals

Virormone (Testosterone propionate) (100-125mg/ml) Generic (non-proprietary)/ Apex/Prochem/Dragon/British Dragon, £14

£20
(10 mls) Pharmaceuticals
Testosterone cypionate 100mg/ml Generic (non-proprietary)/ Apex/Prochem/Dragon/British Dragon,
£17 £25
(10 mls) Pharmaceuticals
Trenbolone acetate;
Trenbolone enanthate Generic (non-proprietary)/ Apex/Prochem/Dragon/British Dragon,
£20 £30
(150 mg/ml) Pharmaceuticals
(10 mls)
Parabolon (trenbolone hexahydrobenzylcarbonate)
(75-150 mg/ml) Negma
(10 mls)
Equitest 400 (testosterone undecanoate 240 mg, boldenone
undecanoate 160 mg/ml) Prochem £20 £30
(10 mls)
Super-tren 2000
(methyltrienolone 2000 mcg/ml) Prochem £27 £50
(10 mls)
Anabolic Steroid Hormones (Oral)
Primobol 50
(Methenolone tablets)
British Dragon Pharmaceuticals £38 £50
50 mg/tablet
30 tabs
Anavar/Oxanobol (oxandrolone)
Generic (non-proprietary)/ Apex/Prochem/Dragon/British Dragon,
10-50 mg/tablet £38 £50
Pharmaceuticals
60 tabs
Winstrol
Generic (non-proprietary)/ Apex/Prochem/Dragon/British Dragon,
(stanozolol) £28 £35
Pharmaceuticals
10-50mg/tablet 50 tabs
Androlic/Anadrol/Oxydrol (Oxymetholone tablets)
Generic (non-proprietary)/ Apex/Prochem/Dragon/British Dragon,
50mg/tablet £28 £60
Pharmaceuticals
60 tablets
Dianabol/Methanobol/DBol (Methandienone/
Generic (non-proprietary)/ Apex/Prochem/Dragon/British Dragon,
Methandrostenolone) 10mg/tablet £40 £55
Pharmaceuticals
(500 tablets)
Peptide Hormones
Hygetropin
(rhGH) Hygene Biopharm Co.,Ltd. £100 £140
100 IU
GenLei® Jintropin™
(rhGH) Gene Science Pharmaceutical Co., Ltd. £100 £140
100 IU
Turbovital
(rhIgf-1) Hygene Biopharm Co.,Ltd. £200 £285
1000 mcg
Growth Hormone Secretagogues
Hexarelin/Sermorelin/Ipamorelin
(growth hormone releasing hormone) ProPeptides Co., Ltd £24 £50
2mg/amp
Myostatin inhibitor
Follistatin 344
Southern Research Co., Ltd £62 £100
(5 mcg)
Black-market Black-market Black-market
Product
Pharmaceutical Manufacturer Wholesale Price Retail Price
Peptide Hormones
Hygetropin
(rhGH) Hygene Biopharm Co.,Ltd. £100 £140
100 IU

J Sports Med Doping Stud Volume 2 • Issue 3 • 1000113

ISSN: 2161-0673 JSMDS, an open access journal
Citation: Graham MR, Davies B, Grace FM, Baker JS (2012) Exercise, Science and Designer Doping: Traditional and Emerging Trends. J Sports Med
Doping Stud 2:113. doi:10.4172/2161-0673.1000113

Page 5 of 9

GenLei® Jintropin™
(rhGH) Gene Science Pharmaceutical Co., Ltd. £100 £140
100 IU
Turbovital
(rhIgf-1) Hygene Biopharm Co.,Ltd. £200 £285
1000 mcg
Growth Hormone Secretagogues
Hexarelin/Sermorelin/Ipamorelin
(growth hormone releasing hormone) ProPeptides Co., Ltd £24 £50
2mg/amp
Myostatin inhibitor
Follistatin 344
Southern Research Co., Ltd £62 £100
(5 mcg)
Table 2:

30% 20 KDa, whereas rhGH is 100% 22 KDa [38]. Research has been development while IGF-1 expression is required for achieving maximal
conducted on rhGH inducing the production of IGF-1 and markers growth.
of collagen metabolism, type 3 pro-collagen (P-III-P), using gender
Factors that are known to cause variation in the levels of IGF-1 in
specific logarithms, but this has yet to be adopted by WADA [39]. GH- the circulation, include genetic make-up, diurnal variation, age, sex,
2000 formulae show reasonable sensitivity, with false-positive rates of exercise status, stress levels, nutrition and disease state.
≤1 in 10,000, but WADA will not adopt immunoassays they do not
own, to prevent commercial companies changing their immunoassays. IGF-1 has an involvement in regulating neurogenesis, myelination,
This is a political decision, not based on scientific discovery and is synaptogenesis, and dendritic branching and neuroprotection after
delaying a robust test which can withstand legal challenge. neuronal damage. The IGF-1 level reflects the secretory activity of
GH and is a marker for identification of normal GH production [44].
A method of cycling the drug, one week on, one week off, using Levels of IGF-1 are at their peak during late adolescence and decline
half strength doses can have significant effects on performance whilst throughout adulthood, mirror imaging GH [45].
thwarting the current detection techniques of the authorities [39].
The stability of the IGF-1 molecule, following administration by
Table 3 identifies genuine rhGH and table 4 identifies potential injection, has been enhanced by combining it with one of its binding
counterfeit rhGH from internet companies. proteins (BP). It is commercially available as rhIGFBP-3 which also
limits adverse effects.
GHRelin (Growth Hormone Secretagogues)
No athlete has yet tested positive for rhIGF and published
Growth Hormone Releasing Hormone (GHRH) induces the knowledge of its use in sport is limited. Tests for detecting it are
synthesis and secretion of growth hormone, and somatostatin currently being processed and consequently athletes have switched to
suppresses the secretion of growth hormone. Growth hormone is also doping with rhIGF as opposed to rhGH.
regulated by ghrelin, a growth hormone secretagogue-receptor ligand
Its effect on physical exercise and anthropometry is being
that is synthesized mainly in the gastrointestinal tract [40]. Twice
investigated, based on similar measurement of markers as rhGH action,
daily administration of ghrelin improved exercise capacity and left
with the hope of being available in time for the 2012 Olympics [46].
ventricular function in patients with chronic heart failure [41]. This
knowledge has initiated the development of companies purporting The concomitant administration of rhGH and rhIGF in GH
to sell growth hormone secretagogues, such as sermorelin and its resistant states has been shown to be synergistic and have effects that are
analogues (table 4). far greater than either alone [44]. Athletes believe that the combination
is more powerful than double of either alone and lower doses of either
Insulin-like Growth Factor-1 (IGF-1) will limit detection (personal communications). Such beliefs appear to
be supported by contemporary research [39,44].
The Insulin-like Growth Factors (IGFs) are proteins with high
sequence similarity to insulin. They are part of a complex system that Table 3 identifies genuine rhIGF and table 4 identifies potential
cells use to communicate with their environment. IGF-1 is mainly counterfeit rhIGF from internet companies.
secreted by the liver and is induced by GH secretion [37]. IGF-1
induces cell proliferation and is thought to inhibit apoptosis [42].
Erythropoietin (Epo)
Erythropoietin (Epo) is a glycoprotein hormone (40% carbohydrate)
It consists of 70 amino acids in a single chain with three intra-
with a Molecular wt of 34 KDa that controls erythropoiesis, in the bone
molecular disulfide bridges. IGF-1 has a molecular weight of 7,649
marrow. It is produced by the peritubular capillary endothelial cells in
daltons. It displays homology to proinsulin, the precursor of insulin the kidney and liver.
[43]. IGF-1 mediates some of the metabolic actions of GH and has
both GH-like and insulin-like actions. Both GH and IGF-1 have a net Recombinant human Erythropoietin (rhEpo) is a synthetic
anabolic effect enhancing whole body protein synthesis, improving analogue of Epo and is commercially available for the treatment of
anthropometry in GHD. Both hormones have been used in catabolism anaemia in humans.
and have been effective in counteracting the protein wasting effects of It was directly identified by urinalysis in 2000, when a test developed
glucocorticoids. IGF-1 administration improves insulin sensitivity, based on immunoelectorphoresis and double blotting (IEF/DB), was
whereas GH therapy can cause compensatory hyperinsulinaemia. endorsed by the IOC and subsequently WADA [47].
IGF-2 is thought to be a primary growth factor required for early The problem in detections is that the duration of the effect on

J Sports Med Doping Stud Volume 2 • Issue 3 • 1000113

ISSN: 2161-0673 JSMDS, an open access journal
Citation: Graham MR, Davies B, Grace FM, Baker JS (2012) Exercise, Science and Designer Doping: Traditional and Emerging Trends. J Sports Med
Doping Stud 2:113. doi:10.4172/2161-0673.1000113

Page 6 of 9

have publicly confessed and have accepted penalties, and a physician

was indicted for distribution of rhEpo, again proving the intricate
involvement between scientists in supplying dopers.

Does rhEpo Enhance Performance?

RhEpo can be administered subcutaneously or intravenously and
has performance-enhancing effects due to the powerful stimulation of
red blood cell production, improving delivery of oxygen to the muscle
tissues.
Exogenous Epo has been shown to increase maximal aerobic
Figure 2: The growth hormone somatropin, in its correct 22-kD-hGH form. power, [55] and maximal oxygen uptake ( V O2max) [48]. Cyclists have
Three-dimensional structure, generated from the protein data base SWISS
PROT. Structural data supplied with the help of the program RasMol. The
confessed to using it throughout their career demonstrating their belief
n-terminal amino acid (at the bottom left hand corner) is marked yellow, as are in its performance enhancing effects and the difficulty in detecting it
the disulphide bridges (and the sequence range missing on the 20 kDa hGH [56].
variant). The ranges with an α-Helix-structure are marked in red.
However, there are dangers to the exercising athlete using rhEpo.
performance is greater than the duration of any haematological changes Arterial systolic blood pressure (SBP) at rest remains unaltered before
associated with rhEpo use. Following discontinuation, red cell mass and after rhEpo admin. During submaximal exercise at 200 watts,
gradually returns to its original state but can take weeks, leaving an corresponding to an average of approx 50% of V O2max, SBP increases
open window where there is no evidence of use but where performance markedly from 177 to 191 mmHg, increasing stress on the heart during
is enhanced [48]. heavy strenuous and prolonged exercise [57]  During competition
cycling and running, the average energy turn-over is often in the range
Testing for rhEpo in urine may seem practical at first sight but of 75-85% of V O2max for long periods.
appears to be a very difficult task because the amount of endogenous
Elevated arterial SBP due to rhEpo injections have been linked
Epo in urine is extremely low [49]. The physiological background for
to unexpected deaths of young cyclists. Within the first four years
testing Epo in urine is complex and the handling of Epo by the renal
of rhEpo’s introduction, this synthetic hormone was suggested to
tubules is poorly understood. Furthermore, exercise-induced renal
have caused over 17 athletes’ deaths [58]. Dr Sandro Donati, an
ischemia and the accompanying post-exercise proteinuria may affect Italian exercise physiologist claims that Italian sport’s phyicians were
the clearance of this peptide hormone. Also, by injecting microdoses administering rhEpo to professional cyclists for large annual fees [59].
of rhEpo, the window of detection can be reduced to as little as 12-18
hours post-injection [50]. Table 3 identifies genuine rhEpo and table 4 identifies potential
counterfeit rhEpo from an internet company.
From 2006, Epo tests at the Olympics have been conducted
on both blood and urine, in an attempt to identify dopers, but the MGF (IGF-1 Ec Peptide)
method officially adopted by WADA for the confirmation of rhEpo
Muscle development must be under the control of local growth
is urinalysis, still based on a combination of IEF/DB. However, the
factors because if a specific muscle is mechanically overloaded, as in
adopted monoclonal anti-Epo antibodies are not mono-specific.
resistant exercise, it is that muscle and not all the muscles that undergo
Therefore, the test can occasionally lead to the false-positive detection
hypertrophy. Mechano growth factor (MGF) has been identified and
of rhEpo (epoetin-beta) in post-exercise, protein-rich urine, and in
appears to be derived from the IGF-1 gene and has a unique C-terminal
cases of contamination of the sample with microorganisms. Up to 20% peptide (IGF-1 Ec peptide). It has a molecular weight of 2868 daltons.
of samples did not show detectable Epo [51]. After resistance exercise, which may cause disruption and damage to
Research was conducted on subjects by adminstering rhEpo for the myofibril cell membranes, the IGF-1 gene predominantly produces
four weeks, with two weeks of “boosting”, followed by two weeks of the IGF-1 splice variant IGF-1 Ec peptide (MGF) which activates
“maintenance” and a post period of three weeks. WADA “Laboratory muscle stem (satellite) cells or muscle progenitor cells that provide the
A” determined rhEpo use in all subjects during the boosting period, extra nuclei required for muscle hypertrophy, repair and maintenance.
whereas WADA “Laboratory B” found no use, with one sample to be The appearance of MGF also up-regulates new protein synthesis. After
negative, and the remaining seven to be suspicious. The detection rates this initial splicing of IGF-1 into MGF, production then switches
decreased throughout the maintenance and post period when total towards producing a systemic release of IGF-1 Ea from the liver, which
hemoglobin mass and exercise performance were elevated. During this also up-regulates protein synthesis. The expression of IGF-1 splice
period, “Laboratory A” found only two of 24 samples to be positive variants, over the course of the regeneration of muscle, following stress,
and three to be suspicious, and “Laboratory B” found no positive or is thought to be the primary anabolic mechanism by which the body
suspicious samples. This study demonstrates a poor correlation in test repairs injuries or produces new muscle. Sarcopaenia and dystrophic
results comparing two WADA-accredited laboratories. Moreover, muscle appear to have an impaired ability to express MGF or refresh
after the initial rhEpo “boosting” period the power to detect rhEpo use the satellite cell pool [60].
during the maintenance and post periods appeared minimal [52]. Unlike mature IGF-1, the distinct E domain of MGF inhibits
terminal differentiation whilst increasing myoblast proliferation.
Any false-positive Epo test concerns by Beullens et al. (2006) [53]
Blocking the IGF-1 receptor with a specific antibody indicates that
have been contested by Catlin et al. (2006) [54] relying on scientific
the function of MGF E domain is mediated via a different receptor,
analytical rigour.
providing localised tissue adaptation and suggesting why loss of muscle
Catlin’s laboratory has reported positive cases for rhEpo, who mass occurs in the elderly and in dystrophic muscle in which MGF

J Sports Med Doping Stud Volume 2 • Issue 3 • 1000113

ISSN: 2161-0673 JSMDS, an open access journal
Citation: Graham MR, Davies B, Grace FM, Baker JS (2012) Exercise, Science and Designer Doping: Traditional and Emerging Trends. J Sports Med
Doping Stud 2:113. doi:10.4172/2161-0673.1000113

Page 7 of 9

Product Pharmaceutical Manufacturer Manufacturers Price Mode of delivery

Genotropin®
net price
(somatropin/rhGH)
Pharmacia 5.3-mg (16-unit) cartridge = £122.87; Subcutaneous/Intramuscular
two-compartment cartridge containing powder for
12-mg (36-unit) cartridge = £278.20
reconstitution
Humatrope®
net price
(somatropin/rhGH)
Lilly 6-mg (18-unit) cartridge =£108.00; Subcutaneous/Intramuscular
two-compartment cartridge containing powder for
24-mg (72-unit) cartridge = £432.00
reconstitution
Norditropin® net price
SimpleXx prefilled solution Novo Nordisk 1.5-mL (5-mg, 15-unit) cartridge = £106.35; Subcutaneous/Intramuscular
(somatropin 3.3 mg; 10 units/mL 1.5-mL (15-mg, 45-unit) cartridge = £319.05
Increlex® (Mecasermin
net price
10 mg/mL; Ipsen Subcutaneous/Intramuscular
4-mL vial = £605.00
Recombinant human insulin-like growth factor-1; rhIGF-1)
Eprex® net price
(prefilled syringe, epoetin alfa) Janssen-Cilag 1000 units = £5.53; Subcutaneous/Intravenous
(Recombinant human erythropoietin; rhEpo) 40 000 units = £265.48
NeoRecormon® net price
(prefilled syringe, epoetin beta) Roche 500 units = £3.75; Subcutaneous/Intravenous
(Recombinant human erythropoietin; rhEpo) 30 000 units = £224.69
Aranesp® net price
Erythropoetin; Amgen 0.4 mL (10 micrograms) = £14.68, Subcutaneous/Intravenous
darbepoetin alfa, 25 micrograms/mL 1 mL (500 micrograms) = £734.05
Table 3: Prescription only Medicines, Peptide hormones used in hormone replacement.

Black-market Black-market Black-market

Product
Pharmaceutical Manufacturer Wholesale Price Retail Price
Peptide Hormones
(Administration by Subcutaneous Injection)
Hygetropin
(rhGH) Hygene Biopharm Co.,Ltd. £100 £140
100 IU
GenLei® Jintropin™
(rhGH) Gene Science Pharmaceutical Co., Ltd. £100 £140
100 IU
Turbovital
(rhIgf-1) Hygene Biopharm Co.,Ltd. £200 £285
1000 mcg
Growth Hormone Secretagogues
Hexarelin/Sermorelin/Ipamorelin
(growth hormone releasing hormones) ProPeptides Co., Ltd £24 £50
2mg/amp

5µg £32; 50µg £82; 1mg 5µg £50; 50µg £100; 1mg
Recombinant Human Erythropoietin-Alpha Prospec Protein Specialist
£940 £1200
Myostatin inhibitor
Follistatin 344
Southern Research Co., Ltd £62 £100
(5 mcg/amp)
Mechano Growth Factor
MGF (C-terminal)
Peptide Labs Research Peptides £18 £50
2 mg amp
Key: amp = ampoule; rhGH = recombinant human growth hormone; rhIgf-1 = recombinant human insulin-like growth factor-1

Table 4: Counterfeit Peptide Hormone Doping Agents.

production is markedly affected [61]. Such potential has attracted the It acts as a negative regulator of skeletal muscle mass. Pharmacological
attention of commercial companies claiming to be able to manufacture agents capable of blocking myostatin activity may have applications for
such peptide hormones for athletic abuse. MGF is available as an promoting muscle growth in human disease. Follistatin, also known as
injectable peptide, and it has been anecdotally shown that injecting it activin-binding protein is a peptide hormone, in humans, encoded by
will increase local muscle growth [62] Research in humans, with MGF the FST gene. Follistatin is an autocrine glycoprotein that is expressed
is currently under consideration. in nearly all tissues. It is part of the inhibin-activin-follistatin axis and
is produced by folliculostellate (FS) cells of the anterior pituitary. In the
Table 4 identifies a potential counterfeit MGF from an internet
company. tissues activin has a strong role in cellular proliferation, thereby making
follistatin the safeguard against uncontrolled cellular proliferation and
A Myostatin Inhibitor (Follistatin) also allowing it to function as an instrument of cellular differentiation.
Both of these roles are vital in tissue rebuilding and repair.
Myostatin is a transforming growth factor-β (TGF-β) family
member that plays an essential role in regulating skeletal muscle growth. Follistatin has been assessed for its role in regulation of muscle

J Sports Med Doping Stud Volume 2 • Issue 3 • 1000113

ISSN: 2161-0673 JSMDS, an open access journal
Citation: Graham MR, Davies B, Grace FM, Baker JS (2012) Exercise, Science and Designer Doping: Traditional and Emerging Trends. J Sports Med
Doping Stud 2:113. doi:10.4172/2161-0673.1000113

Page 8 of 9

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market-place for the acquisition of such products and to negate the 25. Graham MR, Davies B, Grace FM, Kicman A, Baker JS (2008) Anabolic steroid
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J Sports Med Doping Stud Volume 2 • Issue 3 • 1000113

ISSN: 2161-0673 JSMDS, an open access journal
Citation: Graham MR, Davies B, Grace FM, Baker JS (2012) Exercise, Science and Designer Doping: Traditional and Emerging Trends. J Sports Med
Doping Stud 2:113. doi:10.4172/2161-0673.1000113

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